髓系细胞HIF-1信号对结直肠癌的免疫调控效应及肠道微生态机制研究

HIF-1是介导组织和细胞适应低氧环境的关键转录因子，在癌组织和免疫细胞均有表达，但常介导截然相反的效应，这为靶向免疫细胞研究抗肿瘤策略提供依据。结直肠癌是常见的消化系统恶性肿瘤。免疫调控及肠道微生物的改变与肠癌发生发展密不可分。因此，本课题围绕免疫与肠道微生态的互作在肠癌中的调控展开研究。我们前期结果显示，HIF-1α缺失抑制巨噬细胞和中性粒细胞抗感染活性；HIF-1α缺失后可诱Treg和Th1细胞分化并在肠炎等疾病中发挥重要调控效应。而髓系HIF-1β缺失促进髓系抑制细胞集聚并发挥促肠癌生长效应，且与肠道微生态失调明显相关联。本研究中，拟采用HIF-1α和/或HIF-1β髓系细胞条件缺失小鼠观察其在结直肠癌中的免疫细胞发育、分化和功能调控规律、代谢重编程机制及与肠道微生态相互调节的作用机理，从而为靶向HIF-1信号的抗肿瘤免疫治疗策略提供试验依据。

HIF-1 is a key transcription factor in hypoxic environment of cells and tissues. It is expressed differently in cancer tissues and immune cells, which often mediates the opposite effects. These provide a critical basis for the study of anti-tumor strategies targeting immune cells. Colorectal cancer is one of the most common malignant tumors of digestive system, and there is still a lack of effective diagnosis and treatment strategies. There was obvious relationship between immunity, gut microbiota and colorectal cancer. Our previous studies have found that knockout of HIF1-α significantly promotes myeloid cell function differentiation, inhibits macrophage and neutrophil anti-infectious activity. Moreover, knockout of HIF1-α dendritic cells can inhibit IL-12 and promote IL-10 secretion, induce differentiation of Treg and Th1 cells and play an important regulatory role in colitis and other diseases. Knockout of HIF1-β mice promote myeloid cell recruitment and promote the growth of colon cancer, which is significantly associated with intestinal microecological imbalance. In this study, HIF1-α and/or HIF1-β myeloid conditioned deficient mice were used to observe the development, differentiation and functional regulation of immune cells in the colorectum, the mechanism of metabolic reprogramming and the mechanism of interaction with intestinal microecology, so as to provide experimental basis for the study of anti-tumor immunotherapy strategies targeting HIF-1 signal pathway.